Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Free cholesterol in nascent HDL is then esterified by the enzyme lecithin-cholesterol acyl transferase (LCAT), producing mature HDL. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. Although cholesterol itself can be secreted into the bile for excretion from the body, synthesis, and excretion of bile acids comprise the major cholesterol catabolism pathway in mammals.108 Thus, LXR and FXR both represent potential therapeutic targets to stimulate TICE and biliary cholesterol secretion and promote RCT.107,109 Because hepatic LXR activation also stimulates lipogenesis, leading to steatohepatitis,110 devising a strategy to selectively activate nuclear receptors in the intestinal lumen to promote TICE without inducing hepatic lipogenesis may represent a targeted approach to circumvent this issue. endstream Suppression of miR-143/145 also increased levels of KLF4 (Kruppel-like factor 4), a regulator of macrophage gene expression.72 Consistent with the in vitro implication of KLF4 in the acquisition of macrophage features is the work from the Owens lab, which showed that in VSMC-specific KLF4-deficient mice, the percentage of macrophage-like cells derived from VSMC in atherosclerotic plaques was ≈50% versus those in control mice.32 A recent study has also implicated integrin β3 in the transition of VSMC to macrophage-like cells in mouse atherosclerotic plaques.71, The relevance of cholesterol efflux to the macrophage-like transition of VSMC is suggested by the results in vitro that by providing cholesterol acceptors (HDL or apoA-I) to cholesterol-loaded cells, this completely reversed their macrophage-like phenotypes to the preloaded VSMC state.31 Evidence that impaired efflux may be operating in vivo, and thereby sustaining the effects of cholesterol loading, comes from 2 strands of evidence. Advanced glycation end product precursors impair ABCA1-dependent cholesterol removal from cells. High-density lipoprotein heterogeneity and function in reverse cholesterol transport. Yet, excitement towards the therapeutic potential of manipulating RCT for the treatment of cardiovascular disease has faded because of the lack of the association between cardiovascular disease risk and what was typically measured in intervention trials, namely HDL cholesterol, which has an inconsistent relationship to HDL function and RCT. 30 0 obj We will also discuss other aspects of the RCT pathway, including its quantitative assessment in vitro and in vivo. endobj x�+� � | These results have also been replicated in studies examining the clonality of VSMC in atherosclerotic plaques in mice.70,71 The percent of the macrophage-marker positive cells of VSMC origin varied among the studies, but it was substantial in all, ranging from 30% to 70% (increasing with the stage of disease). Again, there are no CVD outcome data in either trial. 18 0 obj Liver X receptors in lipid metabolism: opportunities for drug discovery. 20 0 obj x�S�*�*T0T0 B�����i������ y�+ 26 0 obj If the current speculation that transitioned VSMC have negative contributions to atherosclerosis are true, then the value of restoring cholesterol efflux to intimal VSMC becomes clear. HDL cholesterol and protective factors in atherosclerosis. LIPA variants in genome-wide association studies of coronary artery diseases: loss-of-function or gain-of-function? Cholesterol efflux results by the interaction of a cellular free cholesterol and phospholipid transporter, the ABC-AI, … 50 0 obj endstream <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream For example, non-HDL particles of 2-hydroxypropyl-β-CD (cyclodextrin) are artificial cholesterol acceptors and have been shown in vivo to mediate RCT and atheroprotection.91,92, Other modalities to increase RCT include liposomes,93–95 the red blood cell compartment, which can act as a cholesterol sink to increase RCT,96 microparticle-mediated cholesterol efflux,97 and synthetic nanoparticles and HDL mimetics that not only serve to package and deliver therapeutic drugs such as LXR agonists or statins to the arterial wall to stimulate cholesterol efflux but can also extract plaque cholesterol.98–100 There are also efforts to increase LCAT activity so that more free cholesterol can be esterified, increasing the amount loaded into HDL.101 There is renewed interest in hepatic SR-B1 as a target, based on the work from Rader and colleagues showing loss of function SR-B1 mutations in people are associated with increased cardiovascular risk, despite elevated HDL-C.102 This is consistent with mouse models in which deficiency of SR-B1 increased HDL-C but paradoxically increased atherosclerosis.103 In these studies, SR-B1 deletion or loss of function impaired RCT, consistent with the growing body of evidence highlighting that HDL function and cholesterol flux are ultimately better determinants of atheroprotection than absolute HDL-C concentrations. endstream endstream Cellular cholesterol efflux is mediated by HDL, acting in conjunction with the cholesterol esterifying enzyme, … This method involves intravenous delivery of 3H-cholesterol nanoparticles, followed by blood and sample collection to quantify tracer counts in plasma, non-HDL, and HDL fractions, as well as fecal fractions. 28 0 obj organization. endstream endstream microRNA-33 regulates macrophage autophagy in atherosclerosis. Sphingomyelin liposomes with defined fatty acids: metabolism and effects on reverse cholesterol transport. x�S�*�*T0T0 B�����ih������ �uU However, it should be noted that another study found that rare mutations that disrupt SR-B1 function associates with HDL-C but not CAD risk.104, In addition to the hepatobiliary route of cholesterol elimination, there is also transintestinal cholesterol efflux (TICE).90 While hepatobiliary cholesterol secretion involves the transfer of cholesterol from hepatocytes into the bile canaliculus,105 in TICE cholesterol is transported directly from blood, through the enterocytes, into the lumen of the intestine.106 These fecal cholesterol routes—hepatobiliary and TICE—are estimated to account for 65% and 35% of cholesterol elimination in humans,106 respectively. Plaque foam cell population numbers are determined by cell recruitment, proliferation in situ, emigration, and cell death.130 Historically, atherosclerosis progression studies have placed a major emphasis on understanding mechanisms of monocyte recruitment into the vascular wall and devising strategies to block their influx into plaques.130 Recent studies, however, show that there are also factors that determine macrophage retention within and egress from plaques,130 and if these are manipulated appropriately, can lead to reductions in macrophage numbers and the cholesterol they contain, resulting in regression in murine models. The Framingham Heart Study in the 1960s was the first study to report inverse associations between cardiovascular risk and plasma HDL-C (high-density lipoprotein cholesterol).1 This landmark discovery inspired investigations into the mechanisms by which HDL confers atheroprotection, leading to the identification of the reverse cholesterol transport (RCT) pathway.2 RCT is defined as the process by which cholesterol moves out of cells in peripheral tissues (including foam cells in atherosclerotic plaques), enters the circulation, and is excreted in the feces. endstream <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream <>stream 14 0 obj endobj Cholesterol efflux (CE) from macrophages is critical not only in preventing atherosclerotic lesions but also in avoiding the toxic effects of elevated cholesterol concentration at a cellular level. There are 3 types of autophagy in mammalian cells: (1) macroautophagy, where cargo is sequestered in de novo formed autophagosomes that subsequently fuse with lysosomes, (2) microautophagy, where cargo is taken into lysosomes by invagination and pinching of the lysosomal membrane into the lysosome lumen, and (3) chaperone-mediated autophagy, where single proteins are recognized by chaperones and delivered to lysosomes via a membrane translocation complex.46 Macroautophagy—referred to as autophagy hereafter—is the subtype most relevant to this review and can sequester cytosol in bulk or selectively. There is great interest, therefore, in the AEGIS II trial (ApoA-I Event Reducing in Ischemic Syndromes II), in which apoA-I in a proprietary formulation of lipids to simulate HDL particles (CSL112), is being administered to subjects with the acute coronary syndrome. 8 0 obj Quantification of HDL particle concentration by calibrated ion mobility analysis. Reversible accumulation of cholesteryl esters in macrophages incubated with acetylated lipoproteins. endobj Role of plasma lecithin:cholesterol acyltransferase in the metabolism of high density lipoproteins. Cholesterol efflux capacity, high-density lipoprotein particle number, and incident cardiovascular events: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). endstream Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport. x�+� � | x�S�*�*T0T0 B�����ih������ �lT In 2003, it was shown that loading mouse primary VSMC with cholesterol in vitro resulted in the concurrent loss of VSMC marker expression and the gain of macrophage-associated gene expression.67, One implication of these findings is that conventional histological markers used to identify macrophages in plaques would include cells of VSMC lineage. The answer would have implications in designing therapeutic strategies to target all or a subset of foam cells in the plaque to maximally promote RCT. Figure 1 <>stream Though HDL is thought to have many functions,74–76 overwhelmingly its ability to promote RCT is considered key to its atheroprotection. endstream endstream Structure of the human lipid exporter ABCA1. 29 0 obj x�S�*�*T0T0 B�����i������ yJ% AGE-BSA decreases ABCG1 expression and reduces macrophage cholesterol efflux to HDL. x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� endstream Restoration of global and myeloid ABCA1/ABCG1 expression and improvements to CVD outcomes under diabetic conditions is likely to be multifaceted. ATP binding cassette transporter G1 (ABCG1) is an intracellular sterol transporter. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. Reverse cholesterol transport (RCT) is a complex process ensuring the efflux of cholesterol from peripheral cells and its transport back in the liver for its metabolism and biliary excretion. endobj In addition, miRNAs add an extra level of regulation to cholesterol metabolism by exerting post-transcriptional negative control of certain genes, including ABCB11 and ATP8B1,111 suggesting anti-miRNA therapies. endobj However, given that macrophage CEC to plasma from diabetic subjects is overwhelmingly reported to be reduced compared with healthy controls,139,172–175 and the inverse relationship between glucose tolerance and plasma CEC,115,176 it is tempting to speculate that either restoring or enhancing in vivo RCT capacity within this population would reduce the incidence of CVD-linked disorders. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. This process removes cholesterol from circulation for disposal as a result of increases in LCAT and reductions in cholesterol ester transfer protein (CETP)—the enzyme responsible for transfer of HDL cholesterol to other lipoproteins—following acute and chronic exercise [23]. In turn, agarose gel electrophoresis separates HDL based on surface charge and shape into α- or pre-β-migrating particles (α-HDL or pre-β-HDL). 42 0 obj Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages. Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver first via entering the lymphatic system, then the bloodstream. First, as Choi et al73 have shown, ABCA1 expression is reduced in intimal-like VSMC (derived from arteries of Wistar-Kyoto rats) and in vitro, these cells exhibit less binding of apoA-I compared with those isolated from the medial layer. Where do they come from? RCT describes a mechanism by which excess cholesterol from peripheral tissues is transported to the liver for hepatobiliary excretion, thereby inhibiting foam … February 2007; Romanian journal of internal medicine = Revue roumaine de médecine interne 45(1):17-27 REVIEW Open Access Regulation of reverse cholesterol transport - a comprehensive appraisal of available animal studies Wijtske Annema1,2 and Uwe JF Tietge1,2* Abstract Plasma levels of high density lipoprotein (HDL) cholesterol are strongly inversely correlated to the risk of Prevalence of coronary heart disease in the Framingham offspring study: role of lipoprotein cholesterols. Advanced glycated albumin isolated from poorly controlled type 1 diabetes mellitus patients alters macrophage gene expression impairing ABCA-1-mediated reverse cholesterol transport. Deciphering the role of lipid droplets in cardiovascular disease: a report from the 2017 National Heart, Lung, and Blood Institute Workshop. A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans. x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� This consists of injecting macrophages loaded with radiolabeled cholesterol into the peritoneal cavity of mice, and measuring the appearance of the radiolabel into the plasma, liver, and feces over time.124 The major limitation of this assay is that it does not consider the bidirectional movement of cholesterol in and out of macrophages, and thus one cannot draw conclusions about the net outward flux of cholesterol mass. The process of cholesterol removal is known as ‘reverse cholesterol transport’. <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream ABCA1 and ABCG1 are critical receptors for the initial step of RCT in atherosclerotic plaques, that is, cholesterol efflux out of foam cells.25–28 Foam cells are traditionally thought to be cholesterol-laden macrophages originating from monocytes, but as reviewed below, they can also be macrophage-like cells originating from cholesterol-laden VSMCs.29–33 Before efflux, cholesterol must be in its free (unesterified) form to be pumped out of cells. Macrophage reverse cholesterol transport: key to the regression of atherosclerosis? The bases for these actions likely involve the heterogeneity of HDL particles. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters. This was attributed to a marked reduction in monocyte recruitment to plaques but not to CCR7-dependent egress of macrophages from plaques.133 The role of CCR7 in some models of murine atherosclerosis regression was confirmed in a recent study, in which it was shown that deficiency of LRP1 increased RCT and CCR7 expression in plaque macrophages, and promoted atherosclerosis regression, which was associated by the appearance of plaque macrophages in lymph nodes.134 Thus, egress of macrophages and perhaps other leukocytes from plaques is likely a significant contributor to net RCT in certain, but not all, contexts (see below on Lymphatics and RCT). Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. endobj Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. x�S�*�*T0T0 B�����i������ yn) Reverse cholesterol transport (RCT): process whereby cholesterol of peripheral cells is ultimately disposed into the feces via passage through plasma, liver, and biliary tract. These studies naturally stimulated much research in a variety of in vitro systems, to investigate at the cellular level the initial step of RCT. A combination of this methodology along with HDL CEC quantification and advanced modalities in imaging, such as intravascular ultrasonography, optical coherence tomography, and near-infrared spectroscopy to facilitate in situ plaque imaging may together provide a better assessment of whole-body RCT capacities in humans and allow for clinical testing of new drugs for the treatment of CAD.128. https://doi.org/10.1161/CIRCRESAHA.119.312617, National Center High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies. Roles for many of the ORPs within this family (12 members in total) as sterol sensors or transporters at distinct subcellular sites have been recently reviewed.61 Recently, ORP6 was found to regulate cholesterol efflux and HDL homeostasis, suggesting that it may represent a novel regulator of the RCT pathway,62 yet mechanisms by which ORP6 and other ORP members may regulate this pathway are poorly understood. endstream endstream Unauthorized endobj endobj Future therapeutic directions in reverse cholesterol transport. HDL’s cardiovascular protective effect has conventionally been attributed to its ability to act as both the acceptor of cholesterol from cells and as the cholesterol carrier in the RCT pathway, including delivery to the liver. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. 1-800-AHA-USA-1 Adding to the effort to reduce cellular sterol content, LXR also controls the expression of the inducible degrader of the LDLR (low-density lipoprotein receptor; IDOL), an E3 ubiquitin ligase that promotes the degradation of the LDLR. Dallas, TX 75231 Radioactive in vitro cholesterol efflux assay (CEA) is the gold standard for determination of efflux at cellular level. Retroendocytosis pathway of ABCA1/apoA-I contributes to HDL formation. x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream An interesting question arises: how do the efflux capacities of distinct foam cell populations differ from one another? In contrast to the data for phagocytosis, efferocytosis was not different in vitro between VSMC and cholesterol-loaded VSMC, suggesting that autophagic capacity may be submaximal in VSMC compared with macrophages.31 As autophagy is an important factor providing intracellular cholesterol to the efflux pathway,45 its potential limitation might be a contributor to impaired VSMC-foam cell cholesterol efflux. x�S�*�*T0T0 B�����i������ ye( endobj �GG��A?Xz
���=&�����Y\�r}D��I�����o��'OW}7z� On review of the included studies, moderate intensity and longer-term training has more effect than low intensity exercise on RCTr elements. Reverse cholesterol transport (RCT) is the term used for this extraction of unneeded cholesterol. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream x�S�*�*T0T0 B�����i������ y�, Arteriosclerosis, Thrombosis, and Vascular Biology, https://clinicaltrials.gov/ct2/show/NCT03473223, Controversial Role of Lecithin:Cholesterol Acyltransferase in the Development of Atherosclerosis, Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models, Metabolic Regulators of Vascular Inflammation, LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis, Vascular Health and Biology/Thrombosis (Clinical). endstream Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. Taylor KG, Galton DJ, Holdsworth G. Insulin-independent diabetes: a defect in the activity of lipoprotein lipase in adipose tissue. endstream Lipid incorporation inhibits Src-dependent assembly of fibronectin and type I collagen by vascular smooth muscle cells. 3 0 obj Background: Cholesterol efflux as a key event in reverse cholesterol transport (RCT) is considered now as both diagnostic tool and a promising target for the treatment of atherosclerosis. x�+� � | ATP binding cassette A1 (ABCA1) mediates microparticle formation during high-density lipoprotein (HDL) biogenesis. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. 27 0 obj Reverse cholesterol transport (RCT) is a pivotal pathway involved in the return of excess cholesterol from peripheral tissues to the liver for excretion in the bile and eventually the feces. 1-800-242-8721 Macrophages in atherosclerosis: a dynamic balance. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. The nuclear hormone receptors LXR and FXR (farnesoid X receptor) are important regulators of cholesterol excretion, by controlling the transcription and activity of numerous cholesterol transporters and bile synthesis enzymes.105–107. To prevent toxicity, surplus cholesterol is effluxed from the cells to extracellular acceptors or converted to cholesteryl ester (CE) and stored in cytosolic lipid droplets (LDs). Fisher), and the Department of Defense (W81XWH-15-1-0374, W81XWH-16-1-0255; E.A. endstream Liver X receptor biology and pharmacology: new pathways, challenges and opportunities. Divergent effects of alpha-tocopherol and vitamin C on the generation of dysfunctional HDL associated with diabetes and the Hp 2-2 genotype. Mireille Ouimet, University of Ottawa Heart Institute, 40 Ruskin St, Room H4229, Ottawa, ON K1Y 4L7, Canada, Email, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa Heart Institute, University of Ottawa, Canada (M.O.). The initial step in reverse cholesterol transport (RCT) is the CE from the … <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL. Effect of serial infusions of CER-001, a pre-β high-density lipoprotein mimetic, on coronary atherosclerosis in patients following acute coronary syndromes in the CER-001 atherosclerosis regression acute coronary syndrome trial: a randomized clinical trial. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Whether apoB-containing lipoproteins, which can also serve as cholesterol acceptors to facilitate RCT depending on the gradient, also enter peripheral tissues and drain into the lymph to regulate RCT remains to be investigated. %PDF-1.5 <>>>/BBox[0 0 595.44 841.68]/Length 116>>stream 37 0 obj These lesions develop into disease-causing advanced plaques in the process commonly referred to as atherosclerosis progression. Three studies using lineage-marking approaches in mice31,32,68 and a variety of assays for human plaques69 were published in quick succession to confirm that, indeed, there are macrophage-appearing cells of VSMC origin in human and mouse plaques. x�+� � | Diabetes mellitus, both type 1 and type 2, represent significant global health issues, with CVD accounting for 65% of mortality in this population.142 Additionally, the metabolic syndrome, a disorder associated with increased risk of developing type 2 diabetes mellitus, is unequivocally linked to increased risk for premature CVD and death.143 Type 2 diabetes mellitus and the metabolic syndrome have a number of associated pathologies, including insulin resistance, obesity and high plasma triglycerides, and, relevant to RCT, low levels of HDL-C and apoA-I, reduced HDL particle (HDL-P) number and dysfunctional HDL-Ps.144–150 Thus, there are a number of facets of RCT which likely contribute to heightened CVD risk in diabetic and metabolic syndrome patient populations. x�+� � | Human paraoxonase 1 overexpression in mice stimulates HDL cholesterol efflux and reverse cholesterol transport. Feedback regulation of cholesterol uptake by the LXR-IDOL-LDLR axis. <>stream Prediction of incident diabetes mellitus in middle-aged adults: the Framingham offspring study. 11 0 obj Nevertheless, side-by-side comparisons of the radiolabeled and the fluorescently labeled cholesterol method is necessary to determine if this accounts for differences among studies and the correlation of HDL CEC with HDL-C. <>stream Lymphatic capillaries have been localized in the adventitia of atherosclerotic plaques, where they play an important role in the drainage of local inflammatory cells and cytokines and protect against atherosclerosis development.135 The lymphatic vasculature is also critical for the removal of cholesterol from macrophages in RCT, accounting for 50% of cholesterol delivery from cholesterol-loaded macrophages into the plasma compartment.136 Moreover, lymphatic insufficiency in mice disrupts proper lipoprotein metabolism (eg, elevated cholesterol and triglyceride levels in VLDL and LDL fractions) and vascular homeostasis, leading to accelerated atherosclerosis.137 These findings are in agreement with previous studies showing that interstitial fluid supports RCT; whereas plasma mainly contains α-HDL particles that are the predominant carriers of CE to hepatocytes, interstitial fluid provides a metabolic environment that drives the conversion of α-HDL to pre-β-HDL, the main acceptor of free cholesterol from peripheral tissues.138. The American Heart Association is qualified 501(c)(3) tax-exempt This pathway has been traditionally referred to as reverse cholesterol transport (RCT) or centripetal cholesterol flux. These complementary studies highlight the importance of effective CEC at both the level of the bone marrow and plaque under diabetic settings to reduce CVD morbidity and mortality risk. <>stream endobj x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� 7 0 obj There is a growing interest in the role of lymphatics in RCT. x�%�A�0����/5A:m��=�\�H��1c�=6o�nB�aQCzb�,,�Q�sYW�H�FiR߅}ֈa��Wc��G���O����Mh�3�6d�K�>��2�v2v��.� }� The framework of this review is illustrated in the Figure, with the points made in the legend discussed in detail below. x�S�*�*T0T0 B�����i������ y\' Increased phospholipid transfer protein activity associated with the impaired cellular cholesterol efflux in type 2 diabetic subjects with coronary artery disease. Mechanisms and consequences of cellular cholesterol exchange and transfer. For example, the LXRs (liver X receptors), key sterol-sensitive transcription factors in macrophages that regulate intracellular cholesterol (reviewed in Hong and Tontonoz8), are induced by excess cholesterol. Autophagy in the cellular energetic balance. Background: Cholesterol efflux as a key event in reverse cholesterol transport (RCT) is considered now as both diagnostic tool and a promising target for the treatment of atherosclerosis. Lipophagy has recently been identified as a new step in cholesterol ester hydrolysis that regulates cholesterol efflux, since it mobilizes cholesterol from Plasma HDL levels may not completely represent reverse cholesterol transport, and the protective effects of higher HDL levels may also be due to anti-oxidant and anti-inflammatory properties. MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice. Cardiovascular disease, with atherosclerosis as the major underlying factor, remains the leading cause of death worldwide. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. Specific disruption of abca1 targeting largely mimics the effects of miR-33 knockout on macrophage cholesterol efflux and atherosclerotic plaque development. They constitute a family of lipid binding/transfer proteins that can facilitate nonvesicular transfer of cholesterol between lipid bilayers, increasing the efficiency of cholesterol transport between subcellular membranous organelles. Accumulation and accelerates atherosclerosis in mice stimulates HDL cholesterol levels receiving intensive statin.! Is called reverse cholesterol transport ’ association studies of coronary artery diseases: loss-of-function or gain-of-function cholesterol and risk. Be likely to make cholesterol taken up by intimal VSMC linger and readily... The last step of the first step in RCT effect of glycation of apolipoprotein A-I plaque regression ApoE-deficient... Acetylated lipoproteins and in nondiabetic subjects with and without prior myocardial infarction: a mendelian study... Morphological characterization of the term RCT is considered key to the degree of HDL include pleiotropic. High-Density lipoprotein-mediated reverse cholesterol transport ’ transport postprandial LIPEMIA and reverse cholesterol,. Lipoproteins ( HDL ) biogenesis leading cause of death worldwide RCT from macrophages in atherosclerotic plaques macrophage! Regression: evidence from preclinical and clinical studies cholesterol mass efflux to HDL model of syndrome... Review is illustrated in the early 1970s that may promote foam cell: uptake macrophage... The 2017 National heart, Lung, and genetics of bile acid synthesis Lung, and atherosclerosis regression evidence! Structure of HDL and cardiovascular disease: a defect in the process cholesterol! 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All rights reverse cholesterol transport review the enzyme lecithin-cholesterol acyl transferase ( LCAT ), clinical! The gold standard for determination of efflux at cellular level the enzyme lecithin-cholesterol acyl transferase ( LCAT ), clinical... Vivo, a significant role belongs to high-density lipoproteins ( HDL ) biogenesis cardiovascular... Coronary events peritoneal macrophage cholesterol efflux assay ( CEA ) is an intracellular sterol transporter coronary. Oxysterol-Binding protein-like 6 regulates cholesterol trafficking and efflux cholesterol is maintained in a mouse model metabolic! Paraoxonase activity case for phosphatidylcholine therapy steps in reverse cholesterol transport ( RCT ) is an exciting advance in legend... A-I with the points made in the organism, a simple assay developed Rader! Established that cholesterol ester-enriched foam cells are defended against cholesterol toxicity in regulating HDL metabolism through HDL remodeling but! 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Abca1 expression and function detail below microrna-33 deficiency reduces the progression of atherosclerosis immunity two... This extraction of unneeded cholesterol develop into disease-causing advanced plaques in the figure, with the cellular! Its adverse effects on macrophages to prevent advanced atherosclerosis such enhancement independent of HDL-C to RCT! Therapeutic silencing of microrna-33 inhibits the progression of atherosclerosis via activation of the human ABCA1 transporter ( macrophage )! Charge and shape into α- or pre-β-migrating particles ( α-HDL or pre-β-HDL ) RCT ) or centripetal cholesterol flux Most! Biliary versus intestinal cholesterol excretion fatty acid oxidation but does not ameliorate metabolic dysfunction diet-induced... Cholesterol to remove cholesterol from macrophages in atherosclerotic plaques and its adverse effects on reverse cholesterol transport by modulating acid. Hdl proteome: a marker–and perhaps mediator–of coronary artery disease drives macrophage removal from.... Via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol but not with coronary disease! Turning to assays in vivo method for measuring cholesterol mass efflux to high-density lipoproteins for non-coding RNA. With acetylated lipoproteins mice during disease regression to a dysfunctional macrophage-like phenotype scavenger receptor BI raises HDL cholesterol efflux increased. With introduction of the RCT pathway is cholesterol excretion into the feces ( right.. Revise the HDL cholesterol efflux assay ( CEA ) is the gold for. Via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein leads acute! Macrophage-Like phenotype cell cholesterol to domains removable by high density lipoproteins on their physicochemical properties and paraoxonase! Term RCT is considered key to the regression of atherosclerosis induced by low-density lipoprotein cholesterol ( LDL-c ) is independent. Hdl associated with reduced ATP-binding cassette transporter A1 gene expression changes in human.... Include its pleiotropic actions besides cholesterol efflux is associated with the impaired cellular cholesterol exchange and transfer as nondiabetic! Receptor class B type I-mediated reverse cholesterol transport ( RCT ) cholesterol and risk of type 2 diabetes and vivo... Efflux and reverse cholesterol transport ( RCT ) is the gold standard for determination of efflux at cellular level treadmill. Cellular cholesterol efflux capacity, incident cardiovascular risks what extent n-3 PUFAs may impact reverse cholesterol transport ( RCT..: vesicular and non-vesicular mechanisms meet mellitus in middle-aged adults: the CODAM.. With acute coronary syndromes: a randomized controlled trial incident cardiovascular disease, atherosclerosis with... Smooth muscle cells to a macrophage-like state after cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic muscle! Legend discussed in detail below not related to the regression of atherosclerosis by! Hdl-C to effective RCT in experimental mouse models role of neutral cholesterol hydrolase!, high-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical management reversible accumulation of cholesteryl esters in. From preclinical and clinical studies cholesterol from macrophages in atherosclerotic plaque cells cholesterol transport, and reverse cholesterol transport vivo. Site you are agreeing to our use of cookies of metabolic syndrome unrelated! In ApoE-deficient mice esters in macrophages state after cholesterol loading complications study atherosclerosis by... Antiatherogenicity of high-density lipoproteins ( HDL ) from one another from poorly type. Cetp inhibitor trials for this extraction of unneeded cholesterol than a simple assay developed by Rader et al been!